Extracts of the lemon eucalyptus plant Corymbia citriodora (Eucalyptus citriodora, Eucalyptus maculate var. citriodora) have been used in China under the name Quwenling for the purposes of repelling mosquitoes (Li et al, 1974 Studies on the Repellent Quwenling, Malaria Res., p. 6). The major active repellent ingredient of these extracts has been demonstrated to be p-menthane-3,8-diol (Trigg and Hill, (1996) J Am. Mosq. Control Assoc., 12, 243-246; Trigg and Hill (1996) Phytother., Res., 10, 313-316; Govere et al, (2000), Med., Vet., Entomol., 14, 441-444: Moore et al, (2002 J. Am. Mosq. Control Assoc., 18, 107-110).
Although p-menthane-3,8-diol may be obtained by extraction from the leaves of Corymbia spp., this is economically restricted to the places the plants are growing in sufficient quantity to be commercially viable. As a result, methods of producing p-methane-3,8-diol by chemical synthesis have been proposed.
An early monograph on the synthesis of p-menthane-3,8-diol is given by P. Barbier and G. Leser (1896) (Compt. Rend 124, 1308) who obtain p-menthane-3,8-diol together with isopulegole on the cyclisation of citronellal in dilute sulphuric acid. The reaction probably follows two stages: first the cyclisation of citronellal to isopulegole followed by hydration of the latter material top-menthane-3,8-diol (O. Wallach, Ann., 1908, 360, 102). No mention is made in these early reports of any potential use for the resultant diol.
An essentially similar cyclisation/hydration procedure is described by Zimmerman and English in J. Am. Chem. Soc., 75, 2367 (1953) and this process is followed in U.S. Pat. No. 5,298,250 (R&C Products PTY Ltd) which claims an insect repellent comprising p-menthane-3,8-diol with “synergist acetals”, these acetals are the condensation products of the citronellal starting material and the p-menthane-3,8-diol resulting from the reaction. Although not exhibiting any insect repellent activities per se, U.S. Pat. No. 5,298,250 states that there is a synergism in the insect repellent activity when these acetal compounds are in combination with p-menthane-3,8-diol. The present inventors have been unable to demonstrate such an effect.
U.S. Pat. No. 5,959,161 (Takasago International Corporation) claims a method of producing p-menthane-3,8-diol by treating citronellal with very dilute sulphuric acid but, in other respects, it is essentially the same as the Barbier and Leser method. The claimed high purity of the final p-menthane-3,8-diol is a result of a solvent extraction and recrystallisation procedure.
Thus, compositions comprising p-menthane-3,8-diol are well known. However, physico chemical limitations exist as to the concentration of p-menthane-3,8-diol that may be used in a composition and therefore the efficacy of commercially available products. One major disadvantage of known p-menthane-3,8-diol compositions is that at a concentration of 60% w/w, the p-menthane-3,8-diol becomes supersaturated and therefore crystals will begin to form. Conventionally known products usually avoid this problem by use of a solvent, such as dipropylene glycol and/or by the use of lower concentrations, in the region of 45 to 50%.
We have now surprisingly found a novel composition and a novel process of preparation of p-menthane-3,8-diol which overcomes or mitigates the disadvantages of prior art compositions and process.